Cell Reprogramming During Liver Regeneration

PHILADELPHIA — During embryonic development, animals generate many different types of cells, each with a distinct function and identity.

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Hepatocytes are reprogrammed into biliary cells upon liver injury. Immunofluorescence analysis of yellow fluorescent protein-expressing mouse hepatocytes at 4 weeks after toxin-induced injury. YFP-expressing hepatocytes are green, biliary cells are red, cell nuclei are blue. In the center of the field is a duct containing multiple hepatocyte-derived biliary cells, which appear yellow since are expressing both green and red immunofluorescence.

The adult liver contains two major cell types – hepatocytes and biliary cells – that differ dramatically in appearance and function.Hepatocytes are the main cell type in the liver, where they synthesize proteins and other macromolecules, and detoxify toxic substances. Biliary cells, on the other hand, line the bile ducts, which carry bile from the liver to the small intestine to help digest fats.

Using a sensitive method to tag and track how cells develop and differentiate, the researchers found that conditional expression of an activated Notch1 gene converted hepatocytes into biliary cells. Notch is an important receptor for relaying signals to tell cells how to develop.

What’s more, after the researchers injured liver cells with a variety of toxins to stimulate wound healing, they found that over two to three weeks hepatocytes activated a biliary cell program on their own, acquiring the shape and function of biliary cells. These changes were dependent on the activation of endogenous Notch signaling.

“This is direct evidence that cells can be converted from one mature cell type to another in a live animal, as part of a normal response to injury,” says Stanger. “We think that augmenting pre-existing cell reprogramming relationships may be another way to engineer cells for the treatment of diseases in which there are not enough bile ducts, such as cholestasis.”

Other co-authors are Lara Maggs, Suzanne Shapira, Ravi Maddipati, Nicole Aiello and Rebecca G. Wells, all from Penn, and Linda Greenbaum, from the Jefferson University School of Medicine.

The research was funded by Public Health Services grants (DK083355, DK 090306) and the Pew Charitable Trusts.

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